Gut Microbiota-derived Short-chain Fatty Acids Research Articles

The Diagnostic Potential of Gut Microbiota-Derived Short-Chain Fatty Acids in Preeclampsia.

Preeclampsia (PE) is a complex pregnancy-related hypertensive disorder leading to multiorgan dysfunction. It has high maternal, fetal, and neonatal morbidity and mortality rates. The study of gut microbiota and its metabolites in PE deserves further exploration. Thirty-eight pregnant women with PE and 29 healthy pregnant women in the third trimester of their pregnancy were recruited in this study. We used a targeted metabolomics approach to evaluate the short-chain fatty acids (SCFAs) in serum samples. The correlation between SCFAs and clinical characteristics was also explored. The results of mass spectrometry (MS) showed significant differences at the metabolomics level of SCFAs between the PE and healthy control. The metabolic levels of acetate, propionate, isobutyrate, and valerate were significantly increased in the PE group than in the healthy control group. In contrast, caproic acid and butyrate levels were significantly reduced. The correlation analysis showed that urea, systolic, and diastolic blood pressure levels were positively correlated with four types of SCFAs (acetic acid, propionic acid, isobutyric acid, and valeric acid) which increased in the PE group. Furthermore, the neutrophil percentage and the fetal birth weight were negatively correlated with isobutyric acid and valeric acid. In addition, the receiver operating characteristic (ROC) analysis using a generalized linear model showed that multiple SCFAs would be potential diagnostic markers for PE, with high specificity, sensitivity, and area under the curve (AUC). Among them, isobutyric acid (sensitivity: 97.4%, specificity: 100%, AUC = 1.00), propionic acid (sensitivity: 86.8%, specificity: 93.3%, AUC = 0.954) and acetic acid (sensitivity: 86.8%, specificity: 83.3%, AUC = 0.891) depicted significantly higher diagnostic value and potential clinical applications. In summary, the results of this study indicate that SCFAs have the potential to become effective biomarkers for early screening of PE.

Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC.

Type 3 innate lymphoid cells (ILC3s) are essential for host defense against infection and tissue homeostasis. However, their role in the development of HCC has not been adequately confirmed. In this study, we investigated the immunomodulatory role of short-chain fatty acids (SCFAs) derived from intestinal microbiota in ILC3 regulation. We report that Lactobacillus reuteri was markedly reduced in the gut microbiota of mice with HCC, accompanied by decreased SCFA levels, especially acetate. Additionally, transplantation of fecal bacteria from wild-type mice or L. reuteri could promote an anticancer effect, elevate acetate levels, and reduce IL-17A secretion in mice with HCC. Mechanistically, acetate reduced the production of IL-17A in hepatic ILC3s by inhibiting histone deacetylase activity, increasing the acetylation of SRY (sex-determining region Y)-box transcription factor 13 (Sox13) at site K30, and decreasing expression of Sox13. Moreover, the combination of acetate with programmed death 1/programmed death ligand 1 blockade significantly enhanced antitumor immunity. Consistently, tumor-infiltrating ILC3s correlated with negative prognosis in patients with HCC, which could be functionally mediated by acetate. These findings suggested that modifying bacteria, changing SCFAs, reducing IL-17A-producing ILC3 infiltration, and combining with immune checkpoint inhibitors will contribute to the clinical treatment of HCC.

Interplay between Dysbiosis of Gut Microbiome, Lipid Metabolism, and Tumorigenesis: Can Gut Dysbiosis Stand as a Prognostic Marker in Cancer?

The gut bacterial community is involved in the metabolism of bile acids and short-chain fatty acids (SCFAs). Bile acids are involved in the absorption of fat and the regulation of lipid homeostasis through emulsification and are transformed into unconjugated bile acids by the gut microbiota. The gut microbiota is actively involved in the production of bile acid metabolites, such as deoxycholic acid, lithocholic acid, choline, and SCFAs such as acetate, butyrate, and propionate. Metabolites derived from the gut microbiota or modified gut microbiota metabolites contribute significantly to host pathophysiology. Gut bacterial metabolites, such as deoxycholic acid, contribute to the development of hepatocellular carcinoma and colon cancer by factors such as inflammation and oxidative DNA damage. Butyrate, which is derived from gut bacteria such as Megasphaera, Roseburia, Faecalibacterium, and Clostridium, is associated with the activation of Treg cell differentiation in the intestine through histone acetylation. Butyrate averts the action of class I histone deacetylases (HDAC), such as HDAC1 and HDAC3, which are responsible for the transcription of genes such as p21/Cip1, and cyclin D3 through hyperacetylation of histones, which orchestrates G1 cell cycle arrest. It is essential to identify the interaction between the gut microbiota and bile acid and SCFA metabolism to understand their role in gastrointestinal carcinogenesis including colon, gastric, and liver cancer. Metagenomic approaches with bioinformatic analyses are used to identify the bacterial species in the metabolism of bile acids and SCFAs. This review provides an overview of the current knowledge of gut microbiota-derived bile acid metabolism in tumor development and whether it can stand as a marker for carcinogenesis. Additionally, this review assesses the evidence of gut microbiota-derived short-chain fatty acids including butyric acid in antitumor activity. Future research is required to identify the beneficial commensal gut bacteria and their metabolites which will be considered to be therapeutic targets in inflammation-mediated gastrointestinal cancers.

Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation?

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. It involves the complex interactions between genetic factors, environmental exposure, and gut microbiota. Specific changes in the gut microbiome and metabolome have been described in CRC, supporting the critical role of gut microbiota dysbiosis and microbiota-related metabolites in the tumorigenesis process. Short-chain fatty acids (SCFAs), the principal metabolites generated from the gut microbial fermentation of insoluble dietary fiber, can directly activate G-protein-coupled receptors (GPCRs), inhibit histone deacetylases (HDACs), and serve as energy substrates to connect dietary patterns and gut microbiota, thereby improving the intestinal health. A significantly lower abundance of SCFAs and SCFA-producing bacteria has been demonstrated in CRC, and the supplementation of SCFA-producing probiotics can inhibit intestinal tumor development. SCFAs-guided modulation in both mouse and human CRC models augmented their responses to chemotherapy and immunotherapy. This review briefly summarizes the complex crosstalk between SCFAs and CRC, which might inspire new approaches for the diagnosis, treatment and prevention of CRC on the basis of gut microbiota-derived metabolites SCFAs.

The change of gut microbiota-derived short-chain fatty acids in diabetic kidney disease.

BackgroundPrevious studies found the dysbiosis of intestinal microbiota in diabetic kidney disease (DKD), especially the decreased SCFA‐producing bacteria. We aimed to investigate the concentration of the stool and serum short‐chain fatty acids (SCFAs), gut microbiota‐derived metabolites, in individuals with DKD and reveal the correlations between SCFAs and renal function.MethodsA total of 30 participants with DKD, 30 participants with type 2 diabetes mellitus (DM), and 30 normal controls (NC) in HwaMei Hospital were recruited from 1/1/2018 to 12/31/2019. Participants with DKD were divided into low estimated glomerular filtration rate (eGFR)(eGFR<60ml/min, n=14) and high eGFR (eGFR≥60ml/min, n=16) subgroups. Stool and serum were measured for SCFAs with gas chromatograph‐mass spectrometry.ResultsThe DKD group showed markedly lower levels of fecal acetate, propionate, and butyrate versus NC (p<0.001, p<0.001, p=0.018, respectively) [1027.32(784.21–1357.90)]vs[2064.59(1561.82–2637.44)]μg/g,[929.53(493.65–1344.26)]vs[1684.57(1110.54–2324.69)]μg/g,[851.39(409.57–1611.65)] vs[1440.74(1004.15–2594.73)]μg/g, respectively, and the lowest fecal total SCFAs concentration among the groups. DKD group also had a lower serum caproate concentration than that with diabetes (p=0.020)[0.57(0.47–0.61)]vs[0.65(0.53–0.79)]μmol/L. In the univariate regression analysis, fecal and serum acetate correlated with eGFR (OR=1.013, p=0.072; OR=1.017, p=0.032). The correlation between serum total SCFAs and eGFR showed statistical significance (OR=1.019, p=0.024) unadjusted and a borderline significance (OR=1.024, p=0.063) when adjusted for Hb and LDL. The decrease in serum acetate and total SCFAs were found of borderline significant difference in both subgroups (p=0.055, p=0.050).ConclusionThis study provides evidence that in individuals with DKD, serum and fecal SCFAs levels (fecal level in particular) were lowered, and there was a negative correlation between SCFAs and renal function.

Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Gut microbiota-derived short-chain fatty acids regulate IL-17 production by mouse and human intestinal γδ Tcells.

Gut interleukin-17A (IL-17)-producing γδ Tcells are tissue-resident cells that are involved in both host defense and regulation of intestinal inflammation. However, factors that regulate their functions are poorly understood. In this study, we find that the gut microbiota represses IL-17 production by cecal γδ Tcells. Treatment with vancomycin, a Gram-positive bacterium-targeting antibiotic, leads to decreased production of short-chain fatty acids (SCFAs) by the gut microbiota. Our data reveal that these microbiota-derived metabolites, particularly propionate, reduce IL-17 and IL-22 production by intestinal γδ Tcells. Propionate acts directly on γδ Tcells to inhibit their production of IL-17 in a histone deacetylase-dependent manner. Moreover, the production of IL-17 by human IL-17-producing γδ Tcells from patients with inflammatory bowel disease (IBD) is regulated by propionate. These data contribute to a better understanding of the mechanisms regulating gut γδ Tcell functions and offer therapeutic perspectives of these cells.

ACETATE AMELIORATES GLUCOSE DYSREGULATION AND NEUROBEHAVIOURAL DEFICIT IN DEXAMETHASONE PLUS SCOPOLAMINE-TREATED MICE: GUT-HEART-BRAIN CROSSTALK

Objective: Cardiometabolic disorders have been shown to be associated with the etiology of neurodegenerative diseases but the mechanisms are elusive. There is increasing evidence that the gut microbiota-derived short-chain fatty acids (SCFAs) plays key role in mediating the beneficial effects of the gut microbiome in maintenance of host health. This study was designed to investigate whether SCFA, acetate, would mitigate dexamethasone plus scopolamine-induced dysmetabolism and cognitive decline. Design and method: Male mice (n = 6/group) received (p.o.) vehicle, dexamethasone with scopolamine (DEX; 0.2 mg/kg + SC; 3.0 mg/kg), DEX+SC with sodium acetate (ACE; 200 mg/kg) and DEX+SC with donepezil hydrochloride (DP; 1.0 mg/kg) for 7 days. Morris water maze was used to examine spatial learning and memory while Y-maze was used to determine working and cognitive memory respectively. Oral glucose tolerance test was carried. Results: Degenerative changes such as weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments were noticed in DEX+SC-treated mice compared to control. Furthermore, DEX+SC treatment led to impaired glucose tolerance, elevated 1-hour postload glucose response and increased triglyceride-glucose index. Likewise oxidative impairment was indicated by depleted plasma, cardiac and brain glutathione reductase, nitric oxide and elevated lipid peroxidation (malondialdehyde). Cholinergic deficits characterized by increased neural acetylcholinestrase (AChE) expression and elevated uric acid, lactate dehydrogenase, lactate the plasma, cardiac and neural tissues of the DEX+SC-treated mice further implied cardiac dysfunction alongside the degenerative changes. Consequently, proteolysis was evident by observed diminshed Nissl profiles in axons and dendrites of neurons which correspond to apoptotic changes observed in H&amp;E staining of prefrontal cortex and hippocampal sections. Conclusions: Interestingly, ACE treatment ameliorated the DEX+SC-induced behavioural deficits and cardiometabolic dysfunctions in mice. The effects of ACE treatment were comparable to the DP in DEX+SC-treated rats. Hence, ACE prevents neural and cardiac oxidative damage, behavioural deficits and glucose deregulation. Furthermore, ACE could be a potential AChE inhibitor. These findings suggest that the gut microbiota-derived SCFA, acetate, would be a cost effective therapeutic target for inhibition of neuro-cardiac degenerative processes and behavioural deficits through the gut-heart-brain crosstalk

Gut Microbiota-Derived Short-Chain Fatty Acids Facilitate Microbiota:Host Cross talk and Modulate Obesity and Hypertension.

The purpose of this review is to summarize the evidence supporting a role of short-chain fatty acids (SCFAs) as messengers facilitating cross talk between the host and gut microbiota and discuss the effects of altered SCFA signaling in obesity and hypertension. Recent evidence suggests there to be a significant contribution of gut microbiota-derived SCFAs to microbe:host communication and host metabolism. SCFA production within the intestine modulates intestinal pH, microbial composition, and intestinal barrier integrity. SCFA signaling through host receptors, such as PPARγ and GPCRs, modulates host health and disease physiology. Alterations in SCFA signaling and downstream effects on inflammation are implicated in the development of obesity and hypertension. SCFAs are crucial components of the holobiont relationship; in the proper environment, they support normal gut, immune, and metabolic function. Dysregulation of microbial SCFA signaling affects downstream host metabolism, with implications in obesity and hypertension.

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages.

ABSRTACTKlebsiella pneumoniae is a common cause of human-pneumonia-derived sepsis with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis. The mechanisms by which the gut microbiota affects the host defenses in the respiratory system systematically, however, remain poorly understood. Here, we show that gut microbiota depletion increases susceptibility to extracellular K. pneumoniae infections in terms of increased bacterial burdens in lung and decreased survival rates. Oral supplementation with gut microbiota-derived short-chain fatty acids (SCFAs), subsequently activating G protein-coupled receptor 43 (GPCR43), enhances a macrophage's capacity to phagocytose invading K. pneumoniae Furthermore, SCFAs and GPR43 increase macrophage bacterial clearance by upregulating LAMTOR2, which is further identified as an antibacterial effector and elucidated to facilitate phagosome-lysosome fusion and extracellular signal-regulated kinase (ERK) phosphorylation. Lastly, conditional ablation of Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation.IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.

Dietary Fiber, Genetic Variations of Gut Microbiota-derived Short-chain Fatty Acids, and Bone Health in UK Biobank

Dietary fiber intake may relate to bone health. To investigate whether dietary fiber intake is associated with bone mineral density (BMD), and the modification effect of genetic variations related to gut microbiota-derived short-chain fatty acids (SCFAs). The associations of dietary fiber intake with estimated BMD derived from heel ultrasound and fractures were assessed in 224 630 and 384 134 participants from the UK Biobank. UK Biobank. Estimated BMD derived from heel ultrasound. Higher dietary fiber intake (per standard deviation) was significantly associated with higher heel-BMD (β [standard error] = 0.0047 [0.0003], P = 1.10 × 10-54). Similarly significant associations were observed for all the fiber subtypes including cereal, fruit (dried and raw), and vegetable (cooked and raw) (all P < .05). A positive association was found in both women and men but more marked among men except for dietary fiber in cooked vegetables (all Pinteraction < .05). A protective association was found between dietary fiber intake and hip fracture (hazard ratio, 95% confidence interval: 0.94, 0.89-0.99; P = 3.0 × 10-2). In addition, the association between dietary fiber and heel BMD was modified by genetically determined SCFA propionate production (Pinteraction = 5.1 × 10-3). The protective association between dietary fiber and heel BMD was more pronounced among participants with lower genetically determined propionate production. Our results indicate that greater intakes of total dietary fiber and subtypes from various food sources are associated with higher heel-BMD. Participants with lower genetically determined propionate production may benefit more from taking more dietary fiber.

Dysbiosis of gut microbiota in adult idiopathic membranous nephropathy with nephrotic syndrome

BackgroundGut bacterial microbiota is altered in patients with chronic kidney disease (CKD) and those on dialysis. However, it is not yet clear what bacterial composition changes occur in patients with idiopathic nephrotic syndrome (INS). We present in this report the changes in gut bacterial microbiota in INS patients with membranous nephropathy. MethodsA total of 158 individuals were recruited for this study. Of these, 80 patients had stage 3–5 CKD without nephrotic syndrome (CKD group), 48 patients had INS and pathological diagnosis of membranous nephropathy (INS group), and 30 were age- and sex-matched healthy controls (HC group). The gut microbiome composition was analyzed using a 16S ribosomal RNA gene-based sequencing protocol. ResultsThe results indicate that the nephrotic syndrome patients had a significantly different alpha and beta diversity compared with the CKD group and HC group (P < 0.01). At the phylum level, the INS patients showed increased Fusobacteria and Proteobacteria but reduced Firmicutes when compared with the HC group. At the genus level, Megamonas, Megasphaera, Akkermansia, and the butyrate-producing bacteria Lachnospira, Roseburia, and Fusobacterium were more abundant in the HC group (LDA score > 3) than the CKD and INS group. Fecal organic acid analysis revealed significantly lower quantities of propionate acid and butyric acid in INS than the HC group (P < 0.05). Compared with the HC group, we found that Parabacteroides was increased in CKD and INS patients. In addition, Oscillospira and Ruminococcus were more abundant in CKD patients than in the other two groups (LDA score > 3). At the genus level, ten bacterial taxa were more prevalent in the HC group. Providencia and Myroides were more prevalent in INS patients. ConclusionOur findings highlight that, INS patients had a significantly different alpha and beta diversity and decreased gut microbiota-derived short-chain fatty acids, such as butyrate. However, large-scale prospective studies should be performed to identify the cause and effect factors of these changes in the microbiota in INS patients.

The short-chain free fatty acid receptor FFAR3 is expressed and potentiates contraction in human airway smooth muscle.

Emerging evidence suggests that gut microbiota-derived short-chain fatty acids (SCFAs; acetate, propionate, and butyrate) are important modulators of the inflammatory state in diseases such as asthma. However, the functional expression of the Gi protein-coupled free fatty acid receptors (FFAR2/GPR43 and FFAR3/GPR41) has not been identified on airway smooth muscle (ASM). Classically, acute activation of Gi-coupled receptors inhibits cyclic AMP (cAMP) synthesis, which impairs ASM relaxation and can also induce crosstalk between Gi- and Gq-signaling pathways, potentiating increases in intracellular Ca2+ concentration ([Ca2+]i), favoring ASM contraction. In contrast, chronic activation of Gi-coupled receptors can sensitize adenylyl cyclase resulting in increased cAMP synthesis favoring relaxation. We questioned whether the Gi-coupled FFAR2 or FFAR3 is expressed in human ASM, whether they modulate cAMP and [Ca2+]i, and whether SCFAs modulate human ASM tone. We detected the protein expression of FFAR3 but not FFAR2 in native human ASM and primary cultured human airway smooth muscle (HASM) cells. In HASM cells, acute activation of FFAR3 with SCFAs inhibited forskolin-stimulated cAMP accumulation, but chronic activation did not sensitize cAMP synthesis. SCFAs induced [Ca2+]i increases that were attenuated by pertussis toxin, gallein, U73122, or xestospongin C. Acute treatment with SCFAs potentiated acetylcholine-stimulated [Ca2+]i increases and stress fiber formation in cells and contraction of ex vivo human airway tissues. In contrast, chronic pretreatment of human ASM with propionate did not potentiate airway relaxation. Together, these findings demonstrate that FFAR3 is expressed in human ASM and contributes to ASM contraction via reduced cAMP and increased [Ca2+]i.

Controversial Roles of Gut Microbiota-Derived Short-Chain Fatty Acids (SCFAs) on Pancreatic β-Cell Growth and Insulin Secretion.

In the past 15 years, gut microbiota emerged as a crucial player in health and disease. Enormous progress was made in the analysis of its composition, even in the discovery of novel species. It is time to go beyond mere microbiota-disease associations and, instead, provide more causal analyses. A key mechanism of metabolic regulation by the gut microbiota is through the production of short-chain fatty acids (SCFAs). Acting as supplemental nutrients and specific ligands of two G-protein-coupled receptors (GPCRs), they target the intestines, brain, liver, and adipose tissue, and they regulate appetite, energy expenditure, adiposity, and glucose production. With accumulating but sometimes conflicting research results, key questions emerged. Do SCFAs regulate pancreatic islets directly? What is the effect of β-cell-specific receptor deletions? What are the mechanisms used by SCFAs to regulate β-cell proliferation, survival, and secretion? The receptors FFA2/3 are normally expressed on pancreatic β-cells. Deficiency in FFA2 may have caused glucose intolerance and β-cell deficiency in mice. However, this was contrasted by a double-receptor knockout. Even more controversial are the effects of SCFAs on insulin secretion; there might be no direct effect at all. Unable to draw clear conclusions, this review reveals some of the recent controversies.

Blood Pressure Abnormalities Associated with Gut Microbiota-Derived Short Chain Fatty Acids in Children with Congenital Anomalies of the Kidney and Urinary Tract.

Both kidney disease and hypertension can originate from early life. Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease (CKD) in children. Since gut microbiota and their metabolite short chain fatty acids (SCFAs) have been linked to CKD and hypertension, we examined whether gut microbial composition and SCFAs are correlated with blood pressure (BP) load and renal outcome in CKD children with CAKUT. We enrolled 78 children with CKD stage G1–G4. Up to 65% of children with CAKUT had BP abnormalities on 24 h ambulatory blood pressure monitoring (ABPM). CKD children with CAKUT had lower risk of developing BP abnormalities and CKD progression than those with non-CAKUT. Reduced plasma level of propionate was found in children with CAKUT, which was related to increased abundance of phylum Verrucomicrobia, genus Akkermansia, and species Bifidobacterium bifidum. CKD children with abnormal ABPM profile had higher plasma levels of propionate and butyrate. Our findings highlight that gut microbiota-derived SCFAs like propionate and butyrate are related to BP abnormalities in children with an early stage of CKD. Early assessments of these microbial markers may aid in developing potential targets for early life intervention for lifelong hypertension prevention in childhood CKD.

Regulation of host energy metabolism by gut microbiota-derived short-chain fatty acids

Regulation of host energy metabolism by gut microbiota-derived short-chain fatty acids

Regulatory T Cells Restrict Permeability to Bacterial Antigen Translocation and Preserve Short‐Chain Fatty Acids in Experimental Cirrhosis

Intestinal permeability to translocation of bacterial products is increased in cirrhosis. Regulatory T cells (Tregs) remain central to the interplay between the host and microbial milieu. We propose that Tregs are involved in promoting gut barrier integrity and a balanced interaction with gut microbiota–derived short‐chain fatty acids (SCFAs). Carbon tetrachloride cirrhosis was induced in wild‐type and recombination activating gene 1 (Rag1)‐/‐ mice. Naive T cells and Treg cells were transferred into Rag1 ‐/‐ mice. Intestinal permeability was assessed in vivo after lipopolysaccharide (LPS) oral administration, and bacterial DNA presence was evaluated in mesenteric lymph nodes. Transcript and protein levels of tight‐junction (TJ) proteins were measured in colonic tissue. Intestinal T helper profile in response to Escherichia coli (E. coli) was determined by flow cytometry. SCFAs were measured by gas chromatography–mass spectrometry in colonic content before and after E. coli challenge. Rag1 ‐/‐ mice showed significantly increased permeability to LPS and bacterial DNA translocation rate compared with control mice. Naive T and Treg cotransfer significantly reduced gut permeability to bacterial antigen translocation and restored TJ protein expression in Rag1 ‐/‐ mice. Naive T and Treg replenishment in Rag1 ‐/‐ mice restrained proinflammatory differentiation of intestinal lymphocytes in response to E. coli. The main SCFA concentration resulted in significant reduction in Rag1 ‐/‐ mice after E. coli administration but remained unaltered after naive T and Tregs cotransfer. The reduced expression of SCFA receptors induced by E. coli was reestablished following naive T and Treg reconstitution in Rag1 ‐/‐ mice. Conclusion: The restriction of gut permeability, local inflammatory differentiation, and loss of bacteria‐derived SCFAs foster the value of Tregs in preventing bacterial translocation in cirrhosis.

Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43−/− CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag−/− recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1−/− Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects.

BackgroundGut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism.MethodsHealthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment.ResultsOral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 µmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1).ConclusionsOral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.